Abstract

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines4,5. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and type I IFN-αβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-αβ signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.

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Data deposits

All microarray data are deposited in GEO under accession numbers GSE19491, GSE19444, GSE19443, GSE19442, GSE19439, GSE19435 and GSE 22098. Some of the work has been submitted as US patent application PCT 371: Blood Transcriptional Signature of Mycobacterium Tuberculosis Infection: Serial No: 12/602,488.

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Acknowledgements

We thank the patients and volunteer participants. We thank D. Kioussis (MRC National Institute for Medical Research (NIMR)) and D. Young (NIMR) for discussion and input. We thank N. Baldwin (Baylor Institute for Immunology Research (BIIR)) for advice and support on bioinformatics analysis, Q.-A. Nguyen (BIIR) and colleagues for providing technical assistance with microarray processing, and S. Caidan (NIMR), J. Wills (NIMR) and S. Phillips (BIIR) for help and advice with sample storage and transport. We thank the TB service at Imperial College Healthcare NHS Trust, B.M. Haselden and the TB service at Hillingdon Hospital, Uxbridge, UK. We also thank H. Giedon and R. Seldon for help in laboratory analyses, and Y. Hlombe for recruitment of patients and follow-up in South Africa. A. Rae (NIMR), T. Dipucchio (BIIR) and K. Palucka (BIIR) provided advice on flow cytometry. We thank G. Hayward for help depositing the microarray data. We thank J. Brock (NIMR) for help with graphics. M.P.R.B. was supported by an MRC career development fellowship and a grant from the Dana Foundation Program in Human Immunology. The research was funded by the Medical Research Council, UK, MRC Grant U117565642 and The Dana Foundation Program in Human Immunology. A.O’G., C.M.G. and F.W.McN. are funded by the Medical Research Council, UK. V.P. is supported by National Institutes of Health (NIH) R01 AR050770-01, NIH P50 ARO54083 and NIH 1 U19 AI082715-01. The work of J.B., D.C. and V.P. is supported by the Baylor Health Care System Foundation and the NIH (U19 AIO57234-02, U01 AI082110, P01 CA084512).

Author information

Author notes

    • Christine M. Graham
    •  & Finlay W. McNab

    These authors contributed equally to this work.

Affiliations

  1. Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

    • Matthew P. R. Berry
    • , Christine M. Graham
    • , Finlay W. McNab
    •  & Anne O’Garra
  2. Division of Mycobacterial Research, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

    • Katalin A. Wilkinson
    •  & Robert J. Wilkinson
  3. Department of Respiratory Medicine, St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London W2 1NY, UK

    • Susannah A. A. Bloch
    •  & Onn M. Kon
  4. Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa

    • Tolu Oni
    • , Katalin A. Wilkinson
    •  & Robert J. Wilkinson
  5. Division of Medicine, Wright Fleming Institute, Imperial College, London, W2 1PG, UK

    • Tolu Oni
    •  & Robert J. Wilkinson
  6. Baylor Institute for Immunology Research/ANRS Center for Human Vaccines, INSERM U899, 3434 Live Oak Street, Dallas, Texas 75204, USA

    • Zhaohui Xu
    • , Jason Skinner
    • , Charles Quinn
    • , John J. Cush
    • , Virginia Pascual
    • , Jacques Banchereau
    •  & Damien Chaussabel
  7. Institute for Health Care Research and Improvement, Baylor Health Care System, Dallas, Texas 75206, USA

    • Derek Blankenship
  8. Department of Radiology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London W2 1NY, UK

    • Ranju Dhawan
  9. UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA

    • Romain Banchereau
  10. Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, Ohio 43205, USA

    • Asuncion Mejias
    •  & Octavio Ramilo

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Contributions

M.P.R.B., D.C., O.M.K and A.O’G. designed the study on TB with input from J.B. and R.J.W. and for other diseases with input from V.P. and O.R.; M.P.R.B., S.A.A.B., T.O., K.A.W., J.J.C., A.M., R.B. and O.M.K. recruited, sampled and collected data about patients; M.P.R.B., R.B., A.M. and C.M.G. processed whole blood for microarray experiments with help from J.S.; C.G. performed blood-cell subset separations and processing for microarray experiments with help from J.S.; M.P.R.B., C.M.G. and Z.X. performed microarray data analysis, with advice and input from J.S., D.C. and V.P.; M.P.R.B. and Z.X. performed Ingenuity, modular and ‘molecular distance to health’ analyses; M.P.R.B. performed multiplex serum analyses; F.W.McN. performed flow cytometry analysis; D.C., V.P. and A.O’G. supervised data analysis; M.P.R.B. and D.B. performed statistical analysis; M.P.R.B., S.A.A.B., R.D. and O.M.K performed analyses of radiology; A.O’G. and M.P.R.B. wrote the manuscript, with early input from C.M.G., F.W.McN., J.B., D.C. and J.S., and subsequently all authors provided advice and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Anne O’Garra.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-11 with legends and Supplementary Tables 1.2 .4 and 7 (see separate files for Supplementary Tables 3, 5 and 6).

Excel files

  1. 1.

    Supplementary Table 3

    This table contains 393-transcript list.

  2. 2.

    Supplementary Table 5

    This table contains patient details.

  3. 3.

    Supplementary Table 6

    This table contains 86-transcript list.

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DOI

https://doi.org/10.1038/nature09247

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